Acute, diffuse lung injury often complicates sepsis, gastric acid aspiration, extensive trauma, drug overdose, and other conditions. Clinically, this condition is known as the Adult Respiratory Distress Syndrome (ARDS) that is characterized by catastrophic respiratory failure requiring mechanical ventilation (MV). Although mechanical ventilation is a main stay in managing patients with this condition, several MV-associated complications have been recognized. One of the most serious potential complications of MV is the newly recognized ventilator-induced acute lung injury (VILI). The NIH NHLBI ARDS clinical trials network has just reported that MV strategies employing low tidal volume ventilation reduced mortality in ARDS by 25 percent and lead to a decrease in lung injury and multisystem organ failure. The mechanism by which high volume ventilation causes increased mortality and lung injury is not well understood. In this proposal we will pursue very exciting preliminary results suggesting that matrix metalloproteinases (MMPs) especially gelatinases are responsible for ventilator-induced lung injury in animal lungs subjected to high tidal volume mechanical ventilation. We will also examine the mechanism by which MMPs are up regulated in this type of acute lung injury. Our hypothesis is that Ventilator-induced lung injury is caused by the release and activation of MMPs especially gelatinases. This increase in MMPs is regulated by the cytokine Extracellular matrix metalloproteinase inducer (EMMPRIN) and is caused by the exposure of lung cells to mechanical stress. To prove this hypothesis we have set several specific aims: 1) To systematically examine the induction, release and activation of MMPs especially gelatinases in an experimental rat model of ventilator-induced lung injury (VILI); 2) To examine if MMP inhibitors can prevent ventilator-induced lung injury in rat lungs; 3) To characterize the role of EMMPRIN in VILI; 4) To investigate the influence of mechanical stress as a mechanism of the increased MMP production. This research has significant implications for the management of patients with acute, severe lung injury requiring mechanical ventilation. By better understanding the mechanisms that lead to ventilator-induced lung injury, therapeutic strategies may be devised to improve the outcome in this highly fatal condition.